POS0239 RISK OF VENOUS THROMBOEMBOLIC EVENTS IN PATIENTS WITH RHEUMATOID ARTHRITIS AGED ≥50 YEARS WITH ≥1 CARDIOVASCULAR RISK FACTOR: RESULTS FROM A PHASE 3b/4 RANDOMISED STUDY OF TOFACITINIB VS TUMOUR NECROSIS FACTOR INHIBITORS
Authors: C. Charles-Schoeman, R. M. Fleischmann, E. Mysler, M. Greenwald, C. Wang, A. S. Chen, C. A. Connell, J. Woolcott, S. Menon, Y. Chen, K. Lee, Z. Szekanecz
Journal: Annals of the Rheumatic Diseases (2022)

Background ORAL Surveillance ( NCT02092467 ) was a randomised, open-label, non-inferiority, Phase 3b/4 study assessing the relative risk of major adverse cardiovascular (CV) events (MACE) and malignancies with tofacitinib vs TNF inhibitors (TNFi) in patients (pts) with moderate to severe rheumatoid arthritis despite methotrexate (MTX) and a high risk of MACE (aged ≥50 yrs; ≥1 additional CV risk factor). Objectives To assess risk of venous thromboembolic events (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) in ORAL Surveillance. Methods Pts on stable MTX received tofacitinib 5 or 10 mg twice daily (BID) or a TNFi (etanercept 50 mg weekly or adalimumab 40 mg once every 2 weeks). Incidence rates (IRs; pts with first events/100 pt-yrs [PY]) and 95% CIs were calculated for adjudicated VTE, DVT and PE (overall by 6-month interval and for pts with/without history of VTE). For overall VTE, DVT and PE, numbers needed to harm (NNH; tofacitinib 5 or 10 mg BID vs TNFi) were calculated post hoc. Multivariate Cox models were used post hoc to identify overall independent baseline (BL) risk factors for PE. Censoring time was a 28-day on-treatment period (minimum of last contact date or last study treatment dose date +28 days). Results Analysis included 1455, 1456 and 1451 pts receiving tofacitinib 5 mg BID, 10 mg BID and TNFi, respectively. Generally, across 6-month intervals to &gt;54 months, VTE, DVT and PE IRs were numerically higher with both tofacitinib doses vs TNFi, and with tofacitinib 10 vs 5 mg BID; IRs were consistent across time (data not shown). Across treatments, VTE, DVT and PE IRs were higher in pts with vs without history of VTE; however, only a small number of pts per treatment had history of VTE (Figure 1). NNH for tofacitinib 5 and 10 mg BID, respectively, vs TNFi were 763 and 198 PY for VTE, 1347 and 589 PY for DVT, and 870 and 229 PY for PE, or, over 5 yrs, 153 and 40 pts for VTE, 269 and 118 pts for DVT, and 174 and 46 pts for PE. Identified BL risk factors for PE across treatments included history of VTE, antidepressant use, body mass index ≥30 kg/m 2 , corticosteroid use, male sex, age ≥65 yrs, oral contraceptives/hormone-replacement therapy (HRT) use, and history of hypertension (Table 1). Table 1. Multivariate Cox analyses to identify overall independent BL risk factors for PE across treatments HR (95% CI) p value BL covariate History of VTE 7.06 (2.46, 20.25) 0.0003 Antidepressant use a 2.94 (1.44, 6.02) 0.0032 Body mass index ≥30 kg/m 2 2.97 (1.40, 6.32) 0.0047 Corticosteroid use b 3.01 (1.40, 6.46) 0.0047 Proton pump inhibitor use 0.32 (0.15, 0.71) 0.0052 Male sex c 2.18 (1.06, 4.48) 0.0340 Age ≥65 yrs 2.00 (1.03, 3.88) 0.0401 Oral contraceptives/HRT use 3.56 (1.05, 12.10) 0.0422 History of hypertension 2.57 (0.98, 6.76) 0.0554 a BL antidepressant use was an indicator of an underlying condition of depression, and subgroup analysis did not identify the difference in HRs for depression across treatments b Proxy for elevated BL disease activity; HRs for BL corticosteroid use were similar between all tofacitinib doses combined and TNFi; includes any BL corticosteroid use c Impact of sex on PE risk considered inconclusive Multivariate Cox model using backward selection included treatment effects (not subject to model selection) and overall potential independent risk factors (those affecting PE IRs equally across treatments; subject to model selection) identified from a prior set of Cox regression analyses (which included treatment and a single candidate risk factor in each model fitting, cycling through a predetermined set of risk factors); cut-off for risk factor to stay in multivariate model was p&lt;0.10; nominal p value and HR (95% CI) based on this model HR, hazard ratio Conclusion Generally, in ORAL Surveillance, VTE, DVT and PE IRs were numerically higher for tofacitinib (10 &gt; 5 mg BID) vs TNFi across 6-month intervals, and for pts with vs without history of VTE. Multivariate Cox models identified BL risk factors for PE that may help support future treatment decisions. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by Emma Mitchell, CMC Connect, and funded by Pfizer Inc. Disclosure of Interests Christina Charles-Schoeman Consultant of: AbbVie, Gilead Sciences, Pfizer Inc and Regeneron-Sanofi, Grant/research support from: AbbVie, Bristol-Myers Squibb and Pfizer Inc, Roy M. Fleischmann Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galvani, Gilead Sciences, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis and UCB, Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Flexion, Galapagos, Galvani, Genentech, Gilead Sciences, GSK, Horizon, Janssen, Novartis, Noven, Pfizer Inc, Samumed, Sanofi Aventis, SciSelecta, Teva Pharmaceuticals, UCB, Viela and Vorso, Eduardo Mysler Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, Roche and Sanofi, Grant/research support from: Eli Lilly, Pfizer Inc and Roche, Maria Greenwald Grant/research support from: AbbVie, Eli Lilly, Galapagos, Gilead Sciences, Novartis and Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, All-shine Chen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Carol A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sujatha Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Yan Chen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Kristen Lee Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Zoltán Szekanecz Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Paid instructor for: AbbVie, Eli Lilly, Gedeon Richter, Novartis, Pfizer Inc and Roche, Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Grant/research support from: Pfizer Inc